Post on 18-Dec-2015
I. Solid dispersion
A.Introduction
(1)definition: drug+vehicle
difficultly water-soluble drugs highly disperse in a solid vehicle
states of drugs: molecule, colloidal state, microcrystalline or amorphism
vehicles: water-soluble ones
water-insoluble ones
enteric-soluble ones
(2)properties
(a)increase the dissolution rate and solubility of water-insoluble drugs in order to enhance bioavailability and decrease side-effects in vivo
(b)can make quick-release, sustained-release or enteric-release preparations according to the properties of the vehicles
(c)liquid drugs solid dosage forms
(d)cover (enhance stability and reduce odor)
(d)low dosage and aging
B. Vehicles(1)water-soluble ones PEG: PEG4000, PEG6000 PVP surfactants: poloxamer, PEO,CP organic acids: unsuitable to acid-
sensitive drugs saccharide and alcohols: mannitol celluloses: HPMC, HPC
increasing solubility and dissolution rate of water-immiscible drugs
(2)water-insoluble ones
celluloses: EC
polyactylic resin: Eudragit E, RL, RS
others
sustained release
(3)enteric-soluble ones
celluloses: CAP, HPMCP, CMEC
polyactylic resin: Eudragit L, S
controlled the release site
note: compability
C. Types of solid dispersion
(1)according to the properties of vehicles
quick-release type
sustained-release type
enteric-release type
(2)according to dispersion state of drugs
eutectic mixture: microcrystalline (3)
solid solutions: molecule (1)
coprecipitates: amorphism (2)
D.preparation methods
(1)melting method drug+vehicle(m.p. low, organic solvent-insoluble)
heating
melting
freezing quickly
dosage forms
suitable to drugs and vehicles with promising heat- stability
(2)solvent method drug+vehicle organic solvent solution
evaporate the solvent
coprecipitates
dosage forms suitable to drugs with volatility or
poor stability
(3)solvent-melting method drug+solvent vehicle heating solution melting
mixing
freezing quickly
dosage forms suitable to liquid drugs with low
dosage (lower than 10%)
(4)solvent-spraying (freezing) drying
drug+vehicle
organic solvent
solution
spraying or freezing drying
solid dispersion
suitable to drugs with poor stability
equipment request
(5)others
grinding method
double-spiral extruding method
Note: (1) suitable to drugs with relative low dosage (5-20%)
(2) aging during storage (C of drug, storage conditions and properties of vehicle)
E. Mechanisms of quick- and sustained-release of solid dispersion
(1)quick-release high dispersion of drug (small size
and high energy state) enhanced by vehicles(increase
wettability, keep high dispersion, crystalline-inhibition)
(2)sustained-release water-insoluble vehicles (matrix
diffusion)
II. Inclusion technology
A.Definition
host molecules + guest molecules (space)
inclusion compound
molecular capsules
occlusion compound
adducts
clathrates
host molecules:
1886: hydroquinone
1916: deoxycholic acid
1940: urea
1947: sulfocarbamide
1948: cyclodextrin (CYD)
B. Types
(1)according to structure of host molecules
multi-molecule one
single-molecule one
macro-molecule one
(2)according to shape of host molecules
pipe-shape one
cage-shape one
layer-shape one
C. Mechanism of inclusion
physical combination between host and guest molecules
van der Waals attraction
Structure and polarity of guest molecules should suitable to those of host molecules!
D.CYD inclusion compound
(1)development
1891: be discovered
1948: identify the structure
before 1974: with low yield
1974: scale up and be used widely
(2)structure and properties
O
O
O
O
O
O
O
O O
O
O
O
O
OR
OH
OR
OH
OH
OH
ORHO
HO
RO
HO
HO
HO OH
OHOH
OR
OHHO
HO
RO
β-CYD
index α-CYD β-CYD γ-CYD
Number of glucose6 7 8
Mr 973 1135 1297
Internal diameter0.45~0.6nm 0.7~0.8nm 0.85~1.0nm
Deep of cavity0.7~0.8nm 0.7~0.8nm 0.7~0.8nm
Volume of cavity17.6nm 34.6nm 51.0nm
[α]25D ( H2O )
+150.5° +162.5°+177.4°
S0 ( g/L,25℃ )145 18.5 232
Crystal stateneedle prism prism
(3)preparation techniques
before preparation:
data analysis (possibility)
host choice (α-CYD,β-CYD,γ-CYD)
method choice (indices: yield and drug concentration)
Preparation methods:
saturated water solution method
CYD+water
saturated solution
guest
stirring and mixing
precipitate
filtrating, washing and drying
ultrasonic method mechanical stirring is replaced by
ultrasonics
grinding method CYD+2~5-fold water
paste
drying at low temperature
washing and drying
freezing-drying method
suitable to the soluble inclusion compounds and those with poor heat stability
spray-drying method
suitable to the soluble inclusion compound and those with promising heat stability
impact factors:
ratios of host and guest
preparation methods
T
stirring rate and time
drying methods
determine the optimal conditions by orthogonal experiment
time ( min ) 2 4 6 8 10 15 30 45
I.C.
( %)76.1 85.2 98.2 98.0 98.5 99.2 99.2 99.7
C.T. 7.2 9.2 12.00 13.4 23.5 31.3 60.3 71.8
Dissolution of indomicine from common tablets and inclusion compounds
(5)derivatives of CYD
water-soluble ones:
α-CYD
hydroxyethyl - β- CYD
hydroxypropyl - β- CYD
methyl - β- CYD
branched chain - CYD
poly-CYD
enhancing solubility and reducing irritation
(6)determination of CYD inclusion compounds
microscopy
TLC
UV
DTA and DSC
X-ray diffraction
IR
FC
1HNMR
III.Nanoemulsions and subnanoemulsionsA.Introduction(1)nanoemulsion: d 10-100nm, thermodynamic
stability system appearance high C of emulsifiers (20-30%) mix with water and oil within certain ranges low viscosity low surface tensionFormation mechanism has not been clear
completely.
(2)subnanoemulsion: d 100-500nm, better stability when compared with common emulsions while poorer stability when compared with nanoemulsion
both can be used as drug vehicles!
sustained and prolonged release!
B. Emulsifiers and coemulsifiers
(1)emulsifiers
natural ones: acacia, mucilage tragacanth, gelatine, albumin, casein, lecithin, SP, cholesterol
synthetic ones: Tweens, poloxamers, Spans
(2)coemulsifiers: n-butanol, ethylene glycol, ethanol, propylene glycol, glycerin, poly-glyceride
C.preparation of nanoemulsion
(1)formation comditions
massive emulsifiers:
20-30% of oil
adding coemulsifiers:
adjust the HLB value, insert the interfacial film, form complex agg. film, enhance the degree of rigidity and flexibility, further reduce the interfacial tension, increase the stability of nanoemulsions
(2)steps of preparation
determine the formulation:
ternary phase diagram (p358)
note: keep constant temperature
mixing according to the determined ratios
D.preparation of subnanoemulsion key instrument: high pressure emulsifier impact factors stabilizer: oleic acid enhance the strength of interfacial film increase the solubility of drug increase the absolute value of ξ
potential complex emulsifiers:
lecithin+poloxamer
IV. Microcapsules and microspheres (microparticles)
A.Introduction
(1)definition
polymer+drug
capsulize (membrane wall) -- microcapsules
disperse (matrix) -- microspheres
(2)properties
cover the odors of drugs
enhance the stability
liquid drugs solid
sustained or controlled release
targeting ability
B.Compositions
(1)core material
drug(s)+supplement agents
(2)coating material
natural macromolecule polymers:
gelatin, acacia, alginic acid salts, chitosan
semisynthetic macromolecule polymers:
CMC-Na, CAP, EC, MC, HPMC
synthetic macromolecule polymers:
PLA, PLGA PLA-PEG(biodegradability)
C.Preparation techniques of microcapsules(1)physical-chemical methods (p366) simple coacervation core materials 3%~5%gelatin solution
suspension or emulsion
50 ℃ adjusting pH to 3.5~3.8 by 10%HAc
60%Na2SO4
agg. capsules dilution(Na2SO4 )
sedimented capsules lower than 15 ℃ 37%formaldehyde(pH 8~9 adjusted by 20% NaOH)
solidified capsules washed by water till no formaldehyde remained
microcapsules
preparations
key: polymer solution+polycoagulant (hydrophilic)
lower solubility of polymer
suitable to water-insoluble drugs
complex coacervation: core materials 2.5%~5%gelatin+2.5%~5%acacia
suspension or emulsion
50 ~55℃ 5%HAc adjusting pH to 4.0-4.5
agg. capsules dilution(30~40 water)℃
sedimented capsules lower than 10 ℃ 37%formaldehyde(pH 8~9 adjusted by 20%
NaOH)
solidified capsules washed by water till no formaldehyde remained
microcapsules
preparations note: the differences between simple and
complex coacervation
key:
polymer with positive charge
+
polymer with negative charge
crosslinking
suitable to water-insoluble drugs
solvent-nonsolvent method:
coating material+solvent
solution
nonsolvent
lower the solubility of coating materials
phase separation
remove solvents
suitable to water-soluble and water-insoluble drugs
in-liquid drying:
drug+coating materials+solvent (with low m.p.)
continuous phase+emulsifiers
emulsions evaporating solvent
microcapsules
solvents: acetonitrile, acetone
continuous phase: liquid paraffin
W/O/W multiple emulsion:coating material+organic solvent drug-water solution
(hydrophobic emulsifiers) (thickening agent)
W/O
cooling,+water with
hydrophilic emulsifiers
W/O/W evaporating organic solvent
separation, drying
microcapsules
(2)physical mechanical methods
spray drying:
drug+coating material solution
solution suspension
hot inert gas
microcapsules microspheres
spray congealing:
drug dispersed in melting coating material
spraying in cold gas
coacervation
microcapsules
coating materials: waxes, fatty acid, fatty alcohol
(3)chemical methods
interface polycondensation:
polycondensation occurs on the interface of the disperse phase and the continuous phase resulting in formation of microcapsules
ray-crosslinking method:
gelatin crosslinks under the -ray to form microcapsules
D.Preparation techniques of microspheres(1)gelatin microspheres emulsification crosslinking method
(2)albumin microspheres in-liquid drying, spray drying
(3)starch microshperes emulsification crosslinking method
(4)polyester microspheres in-liquid drying
(5)magnetic microspheres coprecipitation to get magnetic fluid+polymer+drugs
E. factors affecting the size of microparticles
(1)the size of core materials
(2)amount of coating materials
(3)preparation methods
(4)T
(5)stirring rate
(6)concentrations of excipients
(7)viscosity of coating material phase
F. drug release from microparticles diffusion
(1)mechanisms dissolve of coating wall
digestion and degradation of coating wall
(2)impact factors
size
thickness of coating wall
physical chemical properties of vehicles
properties of drugs
preparation conditions and dosage forms
pH of medium
ion strength of medium
G. Quality evaluation
appearance
size and size distribution
drug content
drug-loading rate
entrapment rate
release rate of drug
residual volume of organic solvents
阿糖胞苷水溶液 pH6.9,在60 , 70 , 80℃三个恒温水浴中进行加速实验,求得一级速度常数分别为3.50×10-4/h, 7.97×10-4/h, 1.84×10-3/h,求活化能及 t0.9
V. Nanoparticles (nanocapsules, nanospheres)
A. Properties
(1) Mean size below 100nm
(2) Targeting ability
(3) Improve stability (biomedicines: p.o.)
(4) Prolong the effective time
B. Preparation techniques(1) emulsion polymerization method monomers+water O/W+initiator polymerizatione.g. PACA nanoparticles: (pH, mean MW and C of polymer,
stabilizer, stirring rate, T, emulsifiers)
PMMA nanoparticles: (-ray or initiator, mean MW and C of
polymer, T)
(2) coacervation of natural polymers
chemical crosslinking (albumn)
heating apomorphosis (gelatin)
dehydration (polysaccharides)
(3) in-liquid drying
(4) automatic emulsification
C. Solid lipid nanosheres (SLD)
(1) Properties
high m.p. lipid as matrix
better stability
(2) Preparation methods
melting-homogenization
cold-homogenization
nanoemulsification
D. Others
magnetic nanospheres
modified nanoparticles (hydrophilic agents, MA)
E. Quality evaluation
shape
size and its distribution
entrapment rate and percolation rate
redispersibility
burst-effect (lower than 40% in the first 0.5h)
residual volume of organic solvents
VI. liposomesA. Definition
little bilayering vesicles similar to the structure of biomembrane used as drug vehicles
note: difference between liposomes and micelles
B. Types
SUVs (large and small)
MLVs
note: forming SUVs under ultrasonic condition
C. Compositions
phospholipid+cholestrol
D. Applications
simulation membrane
control drug release (targeting, sustained release, reduce toxicity, enhance stability)
vehicles for genes
E. Physical and chemical characteristics
(1) Phase transition temperature
(2) electricity: +, -, or neutrality
F. Preparation methods
(1) film dispersion method:
lipids+hydrophobic drugs+organic solvents
dissolve
solution
evaporating the solvent by rotation
film PBS (hydrophilic drugs)
hydration to get liposomes
(2) antiphase evaporation method:lipids+organic solvents solution (drugs+water)
3~6 ultrasonic 1
W/O
evaporation
gels
PBS
suspension
suitable to hydrophilic drugs!
(3) infusion method
lipids+hydrophobic drugs+ether
+PBS including hydrophilic drugs (infusion slowly)
ether evaporation (stirring)
MLVs
+high pressure emulsifier
SUVs
(4) others
freezing-drying, ultrasonic dispersion, etc
G. modified liposomes long-circulating liposomes (+hydrophilic polymers to decrease the
swallow of MPS) immunizing liposomes (+MA to improve the targeting ability) glycosyl-liposomes (+glycosyl to enhance the liver targeting) T-sensitive liposomes (depends on the phase transition of lipids) pH-sensitive liposomes (pH-sensitive lipids) magnetic liposomes, sound wave-sensitive
liposomes, etc